Table 1.
The key compound data.
| Cpd ID | BMS986165 | 12 | 15 | |
|---|---|---|---|---|
| Structure |
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| Biochemical assay IC50 (nM) | TYK2(JH1) | 7.5 μM | >10 μM | >16 μM |
| JAK1(JH1) | >10 μM | >10 μM | >16 μM | |
| JAK2(JH1) | >10 μM | >10 μM | >15 μM | |
| JAK3(JH1) | 2.9 μM | >10 μM | >3.4 μM | |
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| IC50 (nM) cell pSTAT3 (TYK2) | 2.8 | 15.3 | 12.1 | |
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| CYP450 inhibition (μM) 1A2/2C9/2C19/2D6/3A4m/3A4t |
>30 | >30/>30/10.4/>30/>30/>30 | >10 | |
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| hERG (μM) | >30 | 50 | 10.6%inhibition@10 μM | |
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| PPB (H/R/M) | 88.0/83.9/76.8 | 96.1/88.9/97.2 | 96.1/NA/94.6 | |
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| Rat PK 10 mpk, po, DMSO: PEG200 | Cmax/AUC/T1/2(1360/9570/3.79) | Cmax/AUC/T1/2(3560/25400/1.88) | NA | |
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| Mouse PK 2%Tween80/0.5%CMC-Na | CL/AUC/t1/2 (18.5/885/2.07) 1mpk, iv Cmax/AUC/T1/2/F% (2390/9350/1.24/69%)15 mpk, po | CL/AUC/t1/2 (11.0/1440/2.8) 1mpk, iv Cmax/AUC/T1/2/F% (3870/25000/1.84/112%)15 mpk, po | Cmax/AUC/T1/2 (12700/53400/1.81) 15 mpk, po | |
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| LMS, H/D/R/M(T1/2,min) | NA/478/316/437 | 1015/164/126/NA | 1613/NA/NA/52 | |
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| Solubility (μM): | PBS (pH 7.4): 4.84 FaSSIF: 94.9 | PBS (pH 7.4): 5.6 FaSSIF: 61.4 | PBS (pH 7.4): >100 FaSSIF: 52.85 | |
Dose (mg/kg); T1/2 (h); CL (mL/min/kg); Cmax (ng/mL); AUC (ng/mL▪h); F (%); iv: intravenous injection; po: peroral administration.